CLEC11A-Driven Molecular Mechanisms in Intervertebral Disc Degeneration: A Comprehensive Multi-Omics Study

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Intervertebral disc degeneration (IVDD) is a prevalent chronic condition with complex genetic and environmental causes.
• The precise genetic mechanisms and key drivers of IVDD pathogenesis remain largely undefined.

Purpose of the Study:

• To identify key pathogenic genes and pathways involved in IVDD using an integrative multi-omics approach.
• To elucidate the cellular mechanisms and mediators underlying IVDD progression.

Main Methods:

• Combined Mendelian randomization (MR) with transcriptomic sequencing to identify IVDD-associated genes.
• Utilized single-cell transcriptomics to pinpoint specific cell types and pathways.
• Performed mediational MR analysis to investigate inflammatory factors and serum metabolites.
• Validated findings through in vitro experiments on nucleus pulposus cells.

Main Results:

• Identified six candidate genes, including CLEC11A, TREM1, and HMGN1, significantly associated with IVDD.
• Single-cell analysis suggested CLEC11A, TREM1, and HMGN1 modulate chondrocyte function and inflammation.
• Mediational MR revealed CLEC11A upregulates inflammatory mediator ARTN and specific serum metabolites, increasing IVDD risk.
• In vitro studies confirmed CLEC11A and ARTN regulate IVDD-related inflammatory markers in nucleus pulposus cells.

Conclusions:

• CLEC11A exacerbates IVDD by upregulating ARTN and inducing metabolic dysregulation.
• This mechanism amplifies inflammatory pathways, driving IVDD progression.
• The findings highlight CLEC11A and ARTN as potential therapeutic targets for IVDD.